Combination of a hypomethylating agent and inhibitors of PARP and HDAC traps PARP1 and DNMT1 to chromatin, acetylates DNA repair proteins, down-regulates NuRD and induces apoptosis in human leukemia and lymphoma cells
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Benigno C. Valdez1, Yang Li1, David Murray2, Yan Liu1, Yago Nieto1, Richard E. Champlin1 and Borje S. Andersson1
1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
2Department of Experimental Oncology, Cross Cancer Institute, Edmonton, Alberta T6G 1Z2, Canada
Benigno C. Valdez, email: firstname.lastname@example.org
Keywords: niraparib; olaparib; decitabine; romidepsin; panobinostat
Received: September 06, 2017 Accepted: November 20, 2017 Published: December 17, 2017
Combination of drugs that target different aspects of aberrant cellular processes is an efficacious treatment for hematological malignancies. Hypomethylating agents (HMAs) and inhibitors of poly(ADP-ribose) polymerases (PARPis) and histone deacetylases (HDACis) are clinically active anti-tumor drugs. We hypothesized that their combination would be synergistically cytotoxic to leukemia and lymphoma cells. Exposure of AML and lymphoma cell lines to the combination of the PARPi niraparib (Npb), the HMA decitabine (DAC) and the HDACi romidepsin (Rom) or panobinostat (Pano) synergistically inhibited cell proliferation by up to 70% via activation of the ATM pathway, increased production of reactive oxygen species, decreased mitochondrial membrane potential, and activated apoptosis. Addition of the DNA alkylating agents busulfan (Bu) and/or melphalan enhanced the anti-proliferative/cytotoxic effects of the triple-drug combination. [Npb+DAC+Rom] significantly increased the level of chromatin-bound PARP1 and DNMT1 and caused acetylation of DNA repair proteins, including Ku70, Ku80, PARP1, DDB1, ERCC1 and XPF/ERCC4. This three-drug combination down-regulated the components of the nucleosome-remodeling deacetylase (NuRD) complex, which is involved in DNA-damage repair. Addition of Bu to this combination further enhanced these effects on NuRD. The trapping of PARP1 and DNMT1 to chromatin, acetylation of DNA repair proteins, and down-regulation of NuRD may all have increased double-strand DNA break (DSB) formation as suggested by activation of the DNA-damage response, concomitantly resulting in tumor cell death. Similar synergistic cytotoxicity was observed in blood mononuclear cells isolated from patients with AML and lymphoma. Our results provide a rationale for the development of [Npb+DAC+Rom/Pano] combination therapies for leukemia and lymphoma patients.
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